Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, and where two C.sub.1 -C.sub.6 alkyl groups are present on one atom, they may be optionally joined to form a C.sub.3 -C.sub.8 cyclic ring optionally including oxygen, sulfur or NR.sub.2a ; PA1 R.sub.2a is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sub.3a and R.sub.3b are independently hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, OR.sub.2, cyano, OCF.sub.3, methylenedioxy, nitro, S(O).sub.m R, CF.sub.3 or C(O)OR.sub.2 and when R.sub.3a and R.sub.3b are in an ortho arrangement, they may be joined to form a C.sub.5 to C.sub.8 aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C.sub.1 -C.sub.10 alkanoyloxy, 1 to 3 C.sub.1 -C.sub.6 alkoxy, phenyl, phenoxy, 2-furyl, C.sub.1 -C.sub.6 alkoxycarbonyl, S(O).sub.m (C.sub.1 -C.sub.6 alkyl); or R.sub.4 and R.sub.5 can be taken together to form --(CH.sub.2).sub.r L.sub.a (CH.sub.2).sub.s -- where L.sub.a is C(R.sub.2).sub.2, O, S(O).sub.m or N(R.sub.2), r and s are independently 1 to 3 and R.sub.2 is as defined above; PA1 R.sub.6 is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 A is: ##STR2## where x and y are independently 0-3; Z is N--R.sub.2 or O; PA1 R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, OR.sub.2, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR.sub.2, 1 to 3 fluoro, S(O).sub.m R.sub.2, C(O)OR.sub.2, C.sub.3 -C.sub.7 cycloalkyl, N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(R.sub.2); or R.sub.7 and R.sub.7a can independently be joined to one or both of R.sub.4 and R.sub.5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R.sub.7 or R.sub.7a groups, wherein the bridge contains 1 to 5 carbons atoms; PA1 B, D, E, and F are independently C(R.sub.8)(R.sub.10), O, C.dbd.O, S(O).sub.m, or NR.sub.9, such that one or two of B, D, E, or F may be optionally missing to provide a 5, 6, or 7 membered ring; and provided that B, D, E and F can be C(R.sub.8)(R.sub.10) or C.dbd.O only when one of the remaining B, D, E and F groups is simultaneously O, S(O)m or NR.sub.9 ; B and D or D and E taken together may be N.dbd.CR.sub.10 -- or CR.sub.10 .dbd.N or B and D or D and E taken together may be CR.sub.8 .dbd.CR.sub.10 provided one of the other of B and E or F is simultaneously O, S(O).sub.m or NR.sub.9 ; PA1 R.sub.8 and R.sub.10 are independently hydrogen, R.sub.2, OR.sub.2, (CH.sub.2).sub.q aryl, (CH.sub.2).sub.q C(O)OR.sub.2, (CH.sub.2).sub.q C(O)O(CH.sub.2).sub.q aryl or (CH.sub.2).sub.q (1H-tetrazol-5-yl) and the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 C.sub.1 -C.sub.8 alkyl, 1 to 3 OR.sub.2 or 1 to 2 C(O)OR.sub.2 ; PA1 R.sub.9 is R.sub.2, (CH.sub.2).sub.q aryl, C(O)R.sub.2, C(O)(CH.sub.2).sub.q aryl, SO.sub.2 R.sub.2, SO.sub.2 (CH.sub.2).sub.q aryl, C(O)N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(CH.sub.2).sub.q aryl, C(O)OR.sub.2, 1-H-tetrazol-5-yl, SO.sub.3 H, SO.sub.2 NHC.tbd.N, SO.sub.2 N(R.sub.2)aryl, SO.sub.2 N(R.sub.2)(R.sub.2) and the (CH.sub.2).sub.q may be optionally substituted by 1 to 2 C.sub.1 -C.sub.4 alkyl, and the R.sub.2 and aryl may be optionally further substituted by 1 to 3 OR.sub.2a, O(CH.sub.2).sub.q aryl, 1 to 2 C(O)OR.sub.2a, 1 to 2 C(O)O(CH.sub.2).sub.q aryl, 1 to 2 C(O)N(R.sub.2a)(R.sub.2a), 1 to 2 C(O)N(R.sub.2a)(CH.sub.2).sub.q aryl, 1 to 5 halogen, 1 to 3 C.sub.1 -C.sub.4 alkyl, 1,2,4-triazolyl, 1-H-tetrazol-5-yl, C(O)NHSO.sub.2 R.sub.2a, S(O).sub.m R.sub.2a, C(O)NHSO.sub.2 (CH.sub.2).sub.q aryl, SO.sub.2 NHC.tbd.N, SO.sub.2 NHC(O)R.sub.2a, SO.sub.2 NHC(O)(CH.sub.2).sub.q aryl, N(R.sub.2)C(O)N(R.sub.2a)(R.sub.2a), N(R.sub.2a)C(O)N(R.sub.2a)(CH.sub.2).sub.q aryl, N(R.sub.2a)(R.sub.2a), N(R.sub.2a)C(O)R.sub.2a, N(R.sub.2a)C(O)(CH.sub.2).sub.q aryl, OC(O)N(R.sub.2a)(R.sub.2a), OC(O)N(R.sub.2a)(CH.sub.2).sub.q aryl; SO.sub.2 (CH.sub.2).sub.q CONH--(CH.sub.2).sub.w NHC(O)R.sub.11, where w is 2-6 and R.sub.11 may be biotin, aryl, or aryl substituted by 1 or 2 OR.sub.2, 1-2 halogen, azido or nitro; PA1 m is 0, 1 or 2; PA1 n is 1 or 2; PA1 q can optionally be 0, 1, 2, 3, or 4; and PA1 G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that at least one is a heteroatom and one of G, H, I or J may be optionally missing to afford 5 or 6 membered heterocyclic aromatic rings; and pharmaceutically acceptable salts and individual diastereomers thereof. PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, and, if two C.sub.1 -C.sub.6 alkyl groups are present on one atom, they may be optionally joined to form a C.sub.4 -C.sub.6 cyclic ring optionally including 1 to 2 heteroatoms selected from oxygen, sulfur or NR.sub.2a ; PA1 R.sub.2a is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sub.3a and R.sub.3b are independently hydrogen, halogen, C.sub.1 -C.sub.4 alkyl, OR.sub.2, methylenedioxy, nitro, S(O).sub.m C.sub.1 -C.sub.4 alkyl, CF.sub.3 or C(O)OR.sub.2 ; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 2 hydroxy, 1 to 2 C.sub.1 -C.sub.6 alkanoyloxy, 1 to 2 C.sub.1 -C.sub.6 alkyloxy or S(O).sub.m (C.sub.1 -C.sub.4 alkyl); PA1 A is: ##STR4## where x and y, are independently 0, 1, or 2; R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.4 alkyl, substituted C.sub.1 -C.sub.4 alkyl where the substituents are from 1 to 3 fluoro or imidazolyl, phenyl, indolyl, S(O).sub.m C.sub.1 -C.sub.4 alkyl, C(O)OR.sub.2 or R.sub.7 and R.sub.7a can independently be joined to one or both of the R.sub.4 and R.sub.5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R.sub.7 or R.sub.7a groups, wherein the bridge contains 1 to 3 carbon atoms; PA1 B, D and F are independently C(R.sub.8)(R.sub.10), O, C.dbd.O, S(O).sub.m or NR.sub.9 such that one of B, D or F may be optionally missing to provide a 5 or 6 membered ting and provided that one of B, D and F is C(R.sub.8)(R.sub.10) or C.dbd.O only when one of the remaining B, D and F groups is simultaneously O, S(O).sub.m or NR.sub.9 ; PA1 R.sub.8 and R.sub.10 are independently hydrogen, R.sub.2, OR.sub.2, (CH.sub.2).sub.q aryl, (CH.sub.2).sub.q C(O)OR.sub.2, (CH.sub.2).sub.q C(O)O(CH.sub.2).sub.q aryl, (CH.sub.2).sub.q (1H-tetrazol-5-yl) and the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 C.sub.1 -C.sub.4 alkyl, 1 to 3 OR.sub.2 or 1 to 2 C(O)OR.sub.2 ; PA1 R.sub.9 is R.sub.2, (CH.sub.2).sub.q aryl, C(O)R.sub.2, C(O)(CH.sub.2).sub.q aryl, SO.sub.2 R.sub.2, SO.sub.2 (CH.sub.2).sub.q aryl, C(O)N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(CH.sub.2).sub.q aryl, 1-H-tetrazolyl-5-yl, SO.sub.2 NHC.tbd.N, SO.sub.2 NR.sub.2 aryl, SO.sub.2 N(R.sub.2)(R.sub.2) and the (CH.sub.2).sub.q may be optionally substituted by 1 to 2 C.sub.1 -C.sub.2 alkyl and the R.sub.2 may be optionally substituted by 1 to 2 OR.sub.2a, O(CH.sub.2).sub.q aryl, 1 to 2 C(O)OR.sub.2a, C(O)N(R.sub.2a)(R.sub.2a), S(O).sub.m R.sub.2a, 1-H-tetrazol-5-yl, C(O)NHSO.sub.2 R.sub.2a, C(O)NHSO.sub.2 (CH.sub.2).sub.q aryl, N(R.sub.2a)C(O)N(R.sub.2a)(R.sub.2a) or N(R.sub.2a)C(O)N(R.sub.2a)(CH.sub.2).sub.q aryl and the aryl may be optionally substituted by 1 to 2 OR.sub.2a, 1 to 2 halogen, 1 to 2 C.sub.1 -C.sub.4 alkyl, C(O)OR.sub.2a or 1-H-tetrazol-5-yl; SO.sub.2 (CH.sub.2).sub.w CONH(CH.sub.2).sub.w NHC(O)R.sub.11, where w=2-6 and R.sub.11 may be biotin, aryl, or aryl substituted by 1 or 2 OR.sub.2, 1-2 halogen, azido or vitro; PA1 m is 0, 1, or 2; PA1 q can optionally be 0, 1, 2 or 3; and the aryl group is phenyl, napthyl, pyridyl, thienyl, indolyl, thiazolyl or pyrimidinyl, and the pharmaceutically acceptable salts and individual diastereomers thereof. PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, and, if two C.sub.1 -C.sub.4 alkyls are present on one atom, they may be optionally joined to form a C.sub.5 -C.sub.6 cyclic ring optionally including the heteroatoms oxygen or NR.sub.2a ; PA1 R.sub.2a is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.3a and R.sub.3b are independently hydrogen, halogen, C.sub.1 -C.sub.4 alkyl, C(O)OR.sub.2, hydroxy, C.sub.1 -C.sub.4 alkoxy, S(O).sub.m C.sub.1 -C.sub.4 alkyl or CF.sub.3 ; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, substituted C.sub.1 -C.sub.4 alkyl where the substituents may be 1 to 2 hydroxy or S(O).sub.m (C.sub.1 -C.sub.3 alkyl); PA1 A is: ##STR6## where x is 0 or 1; R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.3 alkyl; or R.sub.7 and R.sub.7a can independently be joined to one or both of the R.sub.4 and R.sub.5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R.sub.7 or R.sub.7a groups to form 5 or 6 membered rings containing the terminal nitrogen; PA1 B and D are independently C(R.sub.8)(R.sub.10), C.dbd.O, O, S(O).sub.m, NR.sub.9 provided that one of B and D can be C(R.sub.8)(R.sub.10) or C.dbd.O only when the other of B and D is O, S(O).sub.m or NR.sub.9 ; PA1 R.sub.8 and R.sub.10 are independently hydrogen, R.sub.2 or (CH.sub.2).sub.q aryl, and the aryl may be optionally substituted by 1 to 2 of halo, 1 to 2 C.sub.1 -C.sub.4 alkyl, OR.sub.2 or 1 to 2 C(O)OR.sub.2 ; PA1 R.sub.9 is C(O)R.sub.2, C(O)(CH.sub.2).sub.q aryl, SO.sub.2 R.sub.2, SO(CH.sub.2).sub.q aryl, C(O)N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(CH.sub.2).sub.q aryl and the (CH.sub.2).sub.q may be optionally substituted by 1 to 2 C.sub.1 -C.sub.2 alkyl and the R.sub.2 may be optionally substituted by 1 to 2 of OR.sub.2a, O(CH.sub.2).sub.q aryl, C(O)OR.sub.2a, C(O)N(R.sub.2a (R.sub.2a), S(O).sub.m R.sub.2a, 1-H-tetrazol-5-yl, C(O)NHSO.sub.2 R.sub.2a, or N(R.sub.2a)C(O)N(R.sub.2a)(R.sub.2a) and the aryl may optionally be substituted by 1 to 2 OR.sub.2a, 1 to 2 halogen, 1 to 2 C.sub.1 -C.sub.2 alkyl, C(O)OR.sub.2a, 1-H-tetrazol-5-yl or S(O).sub.m R.sub.2a ; PA1 SO.sub.2 (CH.sub.2).sub.q CONH(CH.sub.2).sub.w NHC(O)R.sub.11 where w=2-6 and R.sub.11 may optionally be biotin, aryl, and an aryl be optionally substituted by 1 to 2 OR.sub.2, 1-2 halogen, azido, nitro; PA1 m is 0, 1 or 2; PA1 q can optionally be 0, 1, 2 or 3; PA1 aryl is phenyl, napthyl, pyridyl, indolyl, thienyl or tetrazolyl and the pharmaceutically acceptable salts and individual diastereomers thereof. PA1 R.sub.2 is H, C.sub.1 -C.sub.4 alkyl; PA1 m=1, 2; PA1 t is 0, 1, 2; PA1 q is 1, 2, 3; PA1 w is 2-6;
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carded with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptide analogs for promoting the release of growth hormone which are stable in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.